Oxidative-nitrosative stress in a rabbit pup model of germinal matrix hemorrhage: role of nad(p)h oxidase

Muhammad T. Zia, Anna Csiszar, Nazar Labinskyy, Furong Hu, Govindaiah Vinukonda, Edmund F. Lagamma, Zoltan Ungvari, Praveen Ballabh

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background and purpose-: Germinal matrix hemorrhage-intraventricular hemorrhage is the most common neurological problem of premature infants. Despite this, mechanisms of brain injury from intraventricular hemorrhage are elusive. We hypothesized that germinal matrix hemorrhage-intraventricular hemorrhage, by induction of NAD(P)H oxidases, might cause oxidative/nitrosative stress contributing to brain injuries and that NAD(P)H oxidase inhibition could offer neuroprotection. Methods-: To test this hypothesis, we exploited our rabbit pup model of glycerol-induced germinal matrix hemorrhage-intraventricular hemorrhage. We delivered rabbit pups prematurely (E29) by cesarean section and administered intraperitoneal glycerol at 2 hours postnatal age. Free-radical adducts, including nitrotyrosine, 4-hyroxynonenal, and 8-hydroxy-deoxyguanosine as well as O2 and H2O2 levels were measured in the forebrain. To determine the source of free-radical generation, we used inhibitors for NAD(P)H oxidase (apocynin), xanthine oxidase (allopurinol), cyclo-oxygenase-2 (indomethacin), or nitric oxide synthases (L-NAME). Intraventricular hemorrhage pups were treated with apocynin and cell death was compared between apocynin-treated and vehicle-treated pups. RESULTS-: Nitrotyrosine, 4-hyroxynonenal, and 8-hydroxy-deoxyguanosine levels were higher in pups with intraventricular hemorrhage than controls. Likewise, O2 and H2O2 levels were significantly greater in both the periventricular area and cerebral cortex of pups with intraventricular hemorrhage than controls. In pups with intraventricular hemorrhage, reactive oxygen species production was more in the periventricular area than in the cortex. Apocynin, but not allopurinol, indomethacin, or nitric oxide synthases, inhibited reactive oxygen species generation. Importantly, apocynin reduced cell death in pups with intraventricular hemorrhage. COnclusion-: Activation of NAD(P)H oxidase was the predominant mechanism of free-radical generation in pups with intraventricular hemorrhage. NAD(P)H oxidase inhibition by apocynin might suppress reactive oxygen species production and confer neuroprotection in premature infants with intraventricular hemorrhage.

Original languageEnglish (US)
Pages (from-to)2191-2198
Number of pages8
JournalStroke
Volume40
Issue number6
DOIs
StatePublished - Jun 1 2009
Externally publishedYes

Fingerprint

Oxidoreductases
Oxidative Stress
Hemorrhage
Rabbits
NADPH Oxidase
Free Radicals
Reactive Oxygen Species
Allopurinol
Deoxyguanosine
Premature Infants
Nitric Oxide Synthase
Indomethacin
Glycerol
Brain Injuries
Cell Death
Xanthine Oxidase
NG-Nitroarginine Methyl Ester
Prostaglandin-Endoperoxide Synthases
Prosencephalon
Cesarean Section

Keywords

  • Apocynin
  • Germinal matrix hemorrhage-intraventricular hemorrhage
  • NADPH oxidase
  • Nitrotyrosine
  • Oxidative stress
  • Reactive nitrogen species
  • Reactive oxygen species
  • Superoxide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialized Nursing
  • Medicine(all)

Cite this

Oxidative-nitrosative stress in a rabbit pup model of germinal matrix hemorrhage : role of nad(p)h oxidase. / Zia, Muhammad T.; Csiszar, Anna; Labinskyy, Nazar; Hu, Furong; Vinukonda, Govindaiah; Lagamma, Edmund F.; Ungvari, Zoltan; Ballabh, Praveen.

In: Stroke, Vol. 40, No. 6, 01.06.2009, p. 2191-2198.

Research output: Contribution to journalArticle

Zia, MT, Csiszar, A, Labinskyy, N, Hu, F, Vinukonda, G, Lagamma, EF, Ungvari, Z & Ballabh, P 2009, 'Oxidative-nitrosative stress in a rabbit pup model of germinal matrix hemorrhage: role of nad(p)h oxidase', Stroke, vol. 40, no. 6, pp. 2191-2198. https://doi.org/10.1161/STROKEAHA.108.544759
Zia, Muhammad T. ; Csiszar, Anna ; Labinskyy, Nazar ; Hu, Furong ; Vinukonda, Govindaiah ; Lagamma, Edmund F. ; Ungvari, Zoltan ; Ballabh, Praveen. / Oxidative-nitrosative stress in a rabbit pup model of germinal matrix hemorrhage : role of nad(p)h oxidase. In: Stroke. 2009 ; Vol. 40, No. 6. pp. 2191-2198.
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AU - Hu, Furong

AU - Vinukonda, Govindaiah

AU - Lagamma, Edmund F.

AU - Ungvari, Zoltan

AU - Ballabh, Praveen

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N2 - Background and purpose-: Germinal matrix hemorrhage-intraventricular hemorrhage is the most common neurological problem of premature infants. Despite this, mechanisms of brain injury from intraventricular hemorrhage are elusive. We hypothesized that germinal matrix hemorrhage-intraventricular hemorrhage, by induction of NAD(P)H oxidases, might cause oxidative/nitrosative stress contributing to brain injuries and that NAD(P)H oxidase inhibition could offer neuroprotection. Methods-: To test this hypothesis, we exploited our rabbit pup model of glycerol-induced germinal matrix hemorrhage-intraventricular hemorrhage. We delivered rabbit pups prematurely (E29) by cesarean section and administered intraperitoneal glycerol at 2 hours postnatal age. Free-radical adducts, including nitrotyrosine, 4-hyroxynonenal, and 8-hydroxy-deoxyguanosine as well as O2 and H2O2 levels were measured in the forebrain. To determine the source of free-radical generation, we used inhibitors for NAD(P)H oxidase (apocynin), xanthine oxidase (allopurinol), cyclo-oxygenase-2 (indomethacin), or nitric oxide synthases (L-NAME). Intraventricular hemorrhage pups were treated with apocynin and cell death was compared between apocynin-treated and vehicle-treated pups. RESULTS-: Nitrotyrosine, 4-hyroxynonenal, and 8-hydroxy-deoxyguanosine levels were higher in pups with intraventricular hemorrhage than controls. Likewise, O2 and H2O2 levels were significantly greater in both the periventricular area and cerebral cortex of pups with intraventricular hemorrhage than controls. In pups with intraventricular hemorrhage, reactive oxygen species production was more in the periventricular area than in the cortex. Apocynin, but not allopurinol, indomethacin, or nitric oxide synthases, inhibited reactive oxygen species generation. Importantly, apocynin reduced cell death in pups with intraventricular hemorrhage. COnclusion-: Activation of NAD(P)H oxidase was the predominant mechanism of free-radical generation in pups with intraventricular hemorrhage. NAD(P)H oxidase inhibition by apocynin might suppress reactive oxygen species production and confer neuroprotection in premature infants with intraventricular hemorrhage.

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KW - Superoxide

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